CN115845152A

CN115845152A - Medical instrument

Info

Publication number: CN115845152A
Application number: CN202211475122.7A
Authority: CN
Inventors: 张德元; 齐海萍; 林文娇
Original assignee: Biotyx Medical Shenzhen Co Ltd
Current assignee: Biotyx Medical Shenzhen Co Ltd
Priority date: 2017-02-13
Filing date: 2017-12-28
Publication date: 2023-03-28
Also published as: CN109803693A; WO2018145528A1; CN106798952B; CN106798952A; CN109803693B

Abstract

A medical device comprising a corrodible metal substrate and a ligand-degradable polymer, the ligand-degradable polymer being obtainable by reacting a degradable polymer with a ligand, the ligand-degradable polymer being capable of degrading and releasing a coordinating group capable of coordinating with a corrosion product produced by the corrodible metal substrate in a physiological environment to form a water-soluble coordination compound.

Description

Medical instrument

The present application claims priority of chinese patent application with application number 201710076327.0 entitled "absorbable iron-based internal fixation material for fracture" filed by chinese patent office on 13.02/2017, which is incorporated herein by reference in its entirety.

The technical field is as follows:

the present invention relates to a medical device.

Background art:

currently, implantable medical devices are usually made of metal and its alloy, ceramic, polymer, etc., wherein the metal material is particularly preferred because of its excellent mechanical properties, such as high strength, high toughness, etc. However, corrosion of metal materials may cause two disadvantages: one is the formation of solid corrosion products that are difficult to absorb/metabolize in the body for long periods of time, such as iron-based materials; secondly, higher metal ion concentrations may cause toxicity, such as zinc corrosion to produce zinc ions.

Iron is an important element in the human body and is involved in many biochemical processes, such as oxygen transport. Peuster M and the like take pure iron as a material, and a pure iron stent with a shape similar to that of a clinically used metal stent is manufactured by a laser engraving method and implanted into the descending aorta of a New Zealand rabbit. The results show that no thrombosis complication occurs within 6 to 18 months after the pure iron stent is implanted, no adverse event occurs, and pathological examination proves that the local vascular wall has no inflammatory reaction and smooth muscle cells have no obvious proliferation, which indicates that the implanted device made of the iron-based material has good application prospect. In the prior art, after an absorbable implantable medical device made of pure iron or iron-based alloy is implanted into a body, an iron-based matrix is gradually corroded in physiological solution to generate corrosion products including metal ions and Fe (OH) ₃ 、FeOOH、Fe ₂ O ₃ 、Fe ₃ O ₄ 、 Fe ₃ (PO ₄ ) ₂ And the like solid corrosion products. The solid corrosion products have low solubility, are difficult to dissolve in body fluid, mostly exist in loose precipitation forms, are difficult to be absorbed/metabolized by tissues, so that the absorption period of the medical appliance is overlong, and the solid corrosion products can be remained in the tissues for a long timeThe absorption period of (2).

In addition, metal corrosion also generates free metal ions, which can be cytotoxic when the metal ion concentration is too high. The cytotoxicity (median lethal dose) of zinc ion to fibroblasts, smooth muscle cells and endothelial cells was reported to be at concentrations of 50. Mu. Mol/L, 70. Mu. Mol/L and 265. Mu. Mol/L, respectively.

The ligand is also called as ligand and complexing agent, the ligand structurally contains lone pair electrons or pi electrons as a coordination group, and the coordination group can perform coordination reaction with metal ions to generate a water-soluble coordination compound, reduce the concentration of free metal ions and reduce solid corrosion products (equation (1)).

The prior art discloses that the application of ligands to iron-based alloy medical devices through physical mixing can complex iron corrosion products to some extent, forming water-soluble iron complexes that aid in the removal of iron corrosion products. However, in practical applications, the complexing agent is rarely used due to factors such as solubility and carrying capacity of the complexing agent. For example, water-soluble ligands dissolve away rapidly in body fluids, while the corrosion cycle of iron is longer than 1 year; secondly, the ligand is difficult to form into a film and difficult to load on the surface of the medical device in large quantities.

The invention content is as follows:

based on this, there is a need for a medical device.

A medical device comprising a corrodible metal substrate and a ligand-degradable polymer, wherein the ligand-degradable polymer is obtained by reacting a degradable polymer with a ligand, the ligand-degradable polymer is capable of degrading and releasing a coordinating group, and the coordinating group is capable of performing a coordination reaction with a corrosion product generated by the corrodible metal substrate under a physiological environment to generate a water-soluble coordination compound.

Detailed Description

In order that the invention may be more fully understood, reference will now be made to the following description.

One embodiment of a medical device includes a corrodible metal substrate and a ligand-degradable polymer formed by reacting a degradable polymer with a ligand, the ligand-degradable polymer being capable of degrading and releasing a coordinating group capable of coordinating with a corrosion product produced by the corrodible metal substrate in a physiological environment to form a water-soluble coordination compound.

Further, the material capable of corroding the metal matrix is at least one selected from Fe, zn, mg, iron alloy, zinc alloy and magnesium alloy. Specifically, the corrodible metal substrate is an iron alloy or a zinc alloy. Further, the iron alloy is at least one of an iron-carbon alloy and a nitrided iron alloy. In some embodiments, the iron alloy may also be an iron-based alloy doped with at least one of O, S, P, mn, pd, si, W, ti, co, cr, cu, re; the zinc alloy is doped with at least one of C, N, O, S, P, ce, mn, ca, cu, pd, si, W, ti, co, cr, cu and Re. The Fe content in the ferroalloy is 50-99.99% by mass. The mass percentage of Zn in the zinc alloy is 50-99.99%.

In one embodiment, the corrosion product is a metal ion. Specifically, the metal ions include at least one of iron ions, zinc ions, and magnesium ions.

In one embodiment, the corrosion products further include solid corrosion products. Further, the solid corrosion product is usually Fe (OH) ₃ 、FeOOH、Fe ₂ O ₃ 、Fe ₃ O ₄ 。

In one embodiment, the volume ratio of the ligand-degradable polymer to the corrodible metal matrix is 0.1.

When the medical device is implanted into a living body, the corrodible metal matrix corrodes to generate metal ions or solid corrosion products, and the coordination group in the ligand-degradable polymer and the metal ions or the solid corrosion products undergo a coordination reaction in a physiological environment to generate a water-soluble coordination compound. Compared with the insoluble solid corrosion product, the water-soluble coordination compound can be metabolized and absorbed by organisms more quickly, and is beneficial to the rehabilitation of the lesion part. Meanwhile, the water-soluble coordination compound can greatly degrade the concentration of free metal ions and reduce the risk of cytotoxicity caused by the metal ions.

The medical device may be a vascular stent, a non-vascular endoluminal stent, an occluder, an orthopedic implant, a dental implant, a respiratory implant, a gynecological implant, a male implant, a suture or a bolt. The non-vascular intracavitary stent can be a tracheal stent, an esophageal stent, a urethral stent, an intestinal stent or a biliary stent. The orthopedic implant can be a set screw, set rivet, or bone plate. Of course, other medical devices that need to be degradable and absorbable can be used as the medical device of the present embodiment.

It is understood that both the ligand-degradable polymer and the corrodible metal matrix are biologically acceptable for implantation into an organism.

In some embodiments, the ligand-degradable polymer is at least partially in contact with the corrodible metal matrix. Further, the ligand-degradable polymer may be contacted with the corrodible metal matrix in any one or more of the following ways.

(1) The ligand-degradable polymer forms a coating on the surface of the corrodible metal substrate. Further, the coating is formed by configuring the ligand-degradable polymer into a ligand-degradable polymer solution, and covering the ligand-degradable polymer solution on the surface of the corrodible metal matrix by spraying, dipping, brushing or electrostatic spinning. Of course, the coating may cover only a portion of the surface of the corrodible metal substrate or the entire surface of the corrodible metal substrate. In some embodiments, the ligand-degradable polymer solution further comprises an active drug, such that the resulting coating comprises the ligand-degradable polymer and the active drug mixed with the ligand-degradable polymer. The coating covers 5% -100% of the surface of the corrodible metal matrix. Preferably, the coating covers 100% of the surface of the corrodible metal substrate. The thickness of the coating can be flexibly set according to the specific type of the medical appliance, for example, the size of the coronary stent is small, the thickness of the coating does not exceed 70 micrometers, and the thickness of the coating in the fixing plate can reach 1 mm.

(2) The corrodible metal matrix is provided with a containing part, and the ligand-degradable polymer is contained in the containing part. In some embodiments, the receiving portion is a groove formed on the surface of the corrodible metal substrate, in some embodiments, the receiving portion is a slit formed by the corrodible metal substrate, and in some embodiments, the receiving portion is an inner cavity formed by the corrodible metal substrate. Furthermore, the medical apparatus also comprises an active drug, and the active drug is mixed with the ligand-degradable polymer and then contained in the containing part.

In some embodiments, the medical device is loaded with an active drug. Further, the active drug is mixed with a ligand-degradable polymer. In particular, the two methods described above can be used to load a corrodible metal substrate.

The active drug can be flexibly set according to the application scene and the specific requirements of the medical appliance. In one embodiment, the active agent is selected from at least one of an agent that inhibits vascular proliferation, an anti-platelet agent, an anti-thrombotic agent, an anti-inflammatory agent, and an anti-allergenic agent. The medicine for inhibiting angiogenesis is at least one of paclitaxel, rapamycin and its derivatives. The antiplatelet agent may be cilostazol. The antithrombotic agent may be heparin. The anti-inflammatory agent may be dexamethasone. The anti-sensitization drug is at least one of calcium gluconate, chlorphenamine maleate and cortisone. It should be noted that the above listed drugs are only exemplary, and the selection of various drugs is not limited to the above listed specific drugs, and can be flexibly selected according to the needs.

In one embodiment, the ligand-degradable polymer comprises a degradable polymer and a ligand attached to the degradable polymer. In some embodiments, the ligand-degradable polymer is obtained by reacting a degradable polymer with a ligand. Further, the ligand-degradable polymer is a copolymer of a degradable polymer and a ligand. In the human environment, the ligand-degradable polymer can be degraded and release the coordinating group along with the degradation. Further, the copolymer may be an alternating copolymer, a random copolymer, a block copolymer, or a graft copolymer.

In some embodiments, the degradable polymer has a weight average molecular weight of 1 to 200 ten thousand.

In one embodiment, the degradable polymer is a degradable polyester.

In one embodiment, the degradable polyester is selected from at least one of polylactic acid, polyglycolic acid, polylactic glycolic acid, polycaprolactone, polyhydroxyalkanoate, polyacrylate, polybutylene succinate, poly (beta-hydroxybutyrate), polydioxanone, and polytrimethylene carbonate.

In one embodiment, the degradable polyester is selected from degradable copolymers, wherein the degradable copolymers are selected from copolymers formed by copolymerization of at least two of the monomers forming polylactic acid, polyglycolic acid, polylactic glycolic acid, polycaprolactone, polyhydroxyalkanoate, polyacrylate, polybutylene succinate, poly (beta-hydroxybutyrate), polydioxanone, and polytrimethylene carbonate. It should be noted that other biodegradable and biologically safe materials that bind to the ligand can be used as the degradable polymer.

In some embodiments, the ligand-degradable polymer comprises 5% to 80% by weight of the ligand. If the mass percentage of the ligand is less than 5 percent, the amount of the coordination groups released by the degradation of the ligand-degradable polymer is too small, so that only a small amount of corrosion products can be complexed, and the practical significance is not great; if the mass percentage of the ligand is more than 80%, the structure of the degradable polymer may be damaged.

The ligand only needs to be capable of generating a coordination reaction with a corrosion product generated by a corrodible metal matrix under a physiological environment to generate a water-soluble coordination compound. In some embodiments, the water-soluble coordination compound has a solubility of greater than or equal to 10mg/L in PBS buffer at 36 ℃ to 38 ℃. Furthermore, the solubility of the water-soluble coordination compound in PBS buffer solution at 36-38 ℃ is 10-100 mg/L. When the solubility of the complex compound in physiological solution is greater than or equal to 100mg/L, it indicates that the complex compound can rapidly diffuse and be metabolized in a physiological environment. When the solubility of the complex compound in a physiological solution is in the range of 10mg/L to 100mg/L, although the complex compound precipitates when the concentration of the complex compound in the solution reaches saturation, the complex compound in the precipitated state is dissolved again until all the complex compound is completely dissolved and absorbed and metabolized by tissues of an animal as the complex compound dissolved in the physiological solution gradually diffuses and is absorbed and metabolized by the tissues of the animal, breaking the equilibrium of dissolution. Therefore, this example defines a complex compound having a solubility in a physiological solution of 10mg/L or more as a water-soluble complex compound.

In one embodiment, the coordinating group contains at least one of amino, carboxyl, cyanide, thiocyanate, isothiocyanide, nitro, hydroxyl, phenolic hydroxyl, mercapto (-SH), carbonyl, heteroaromatic groups, nitroso, sulfo, phosphate, and organophosphine groups. Further, the ligand group contains at least one of an amino group and a carboxyl group. Further, the ligand containing carbonyl group is selected from at least one of carboxylic acid, carboxylate, anhydride, ester, amide, polycarboxylic acid and polyanhydride.

Further, the aromatic heterocyclic group is at least one selected from the group consisting of furyl, pyrrolyl, thienyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridonyl, pyranyl, pyronyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, phthalazinyl, pteridinyl, indolyl, purinyl and phenanthrolinyl.

Furthermore, the ligand is a polydentate ligand containing at least two coordinating groups, and the generated coordinating groups can form a chelate with metal ions. Further, the generated coordinating group can form a chelate with iron ions or zinc ions under physiological environment.

In one embodiment, the polydentate ligand is at least one of a polydentate ligand containing a hydroxyl group on the fused ring aromatic hydrocarbon, a polydentate ligand containing a mercapto group, a polydentate ligand containing an amino group, a polydentate ligand containing an aromatic heterocyclic group, a polydentate ligand containing a nitroso group, a polydentate ligand containing a carbonyl group, a polydentate ligand containing a sulfo group, a polydentate ligand containing a phosphoric acid group, a polydentate ligand containing an organic phosphine group, and a polydentate ligand containing a carbonyl group.

Further, the polydentate ligand that contains hydroxyl groups on the polycyclic aromatic hydrocarbon is at least one member selected from the group consisting of 8-hydroxyquinoline, 8-hydroxyquinaldine, sodium 4, 5-dihydroxybenzene-1, 3-disulfonate, and 4- [3, 5-bis-hydroxyphenyl-1H-1, 2, 4-triazole ] -benzoic acid (deferasirox). The multi-dentate ligand containing sulfydryl is at least one selected from 8-mercaptoquinoline, thioglycolic acid and methyl 5-methyl-2-mercaptobenzoate. The multidentate ligand containing amino group is at least one selected from ethylenediamine, butanediamine, spermidine, spermine, triethylene tetramine, ethylenediamine tetraacetic acid, tetrasodium ethylenediamine tetraacetate and N' - [5- [ [4- [ [5- (acetylhydroxyamino) pentyl ] ammonia ] -1, 4-dioxybutyl ] hydroxylamine ] pentyl ] -N- (5-aminopentyl) -N-hydroxysuccinamide (deferoxamine). The polydentate ligand containing an aromatic heterocyclic group is at least one member selected from the group consisting of phenanthroline, bipyridine, porphyrin, porphine, chlorophyll, hemoglobin, and 1, 2-dimethyl-3-hydroxy-4-pyridone (deferiprone). The multidentate ligand containing nitroso is at least one selected from 1-nitroso-2-naphthol and 1-nitroso-2-naphthol-6-sodium sulfonate. The carbonyl-containing polydentate ligand is at least one member selected from the group consisting of polycarboxylic acids and salts thereof, anhydrides, esters, amides, polycarboxylic acids, and polyanhydrides. The multidentate ligand containing sulfo group is at least one selected from sulfosalicylic acid and 8-hydroxyquinoline-5-sulfonic acid. The polydentate ligand containing a phosphate group is at least one selected from pyrophosphoric acid, tripolyphosphoric acid, hexametaphosphoric acid, polyphosphoric acid, sodium pyrophosphate, sodium hexametaphosphate and ammonium polyphosphate. The polydentate ligand containing organic phosphine groups is at least one selected from potassium diethylenetriamine pentamethylene phosphonate and sodium ethylene diamine tetramethylene phosphonate. The carbonyl-containing polydentate ligand is selected from at least one of oxalic acid, tartaric acid, malic acid, succinic acid, oxaloacetic acid, fumaric acid, maleic acid, citric acid, nitrilotriacetic acid, diethylenetriaminepentacarboxylic acid, alginic acid, glutamic acid, aspartic acid, ornithine, lysine, maleic anhydride, acetic anhydride, maleic anhydride, succinic anhydride, maleic anhydride, phthalic anhydride, potassium citrate, calcium citrate, glycerol citrate, acetylsalicylic acid, sulfosalicylamide, polyaspartic acid, polyglutamic acid, polyornithine, polylysine, and polymaleic anhydride.

In one embodiment, the polydentate ligand is selected from at least one of amino acid, oligopeptide, polypeptide, protein, polyamine, anhydride and polyanhydride containing amino or carboxyl groups. Among them, peptides are compounds formed by dehydrating amino acids and then linking them together by peptide bonds, and peptides consisting of 2 to 10 amino acids are called oligopeptides, peptides consisting of 10 to 50 amino acids are called polypeptides, and peptides consisting of 50 or more amino acids are called proteins. Specifically, the amino acid is at least one selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, asparagine, glutamic acid, lysine, glutamine, methionine, serine, threonine, ornithine, cysteine, proline, histidine and arginine.

In one embodiment, the ligand is selected from polysaccharides containing multiple hydroxyl groups. Specifically, the polysaccharide is at least one selected from the group consisting of dextran, chitosan, plant polysaccharide, starch, dextrin, cellulose, glycogen, chitin, inulin, agar, gum arabic, hyaluronic acid, gellan gum, curdlan, xanthan gum, pectin, konjac glucomannan, gum arabic, algal lichenin, alginate, spirulina polysaccharide, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin, and heparan sulfate.

In some embodiments, the ligand-degradable polymer is obtained by reacting a ligand with a degradable polymer, the ligand containing a carbon-carbon double bond (=). Specifically, the ligand is at least one selected from 2-amino-4-pentenoic acid, 2-acetamidoacrylic acid, maleic acid, fluoroelenic acid, allyl oxalate, octenylsuccinic acid, diethylenetriamine pentacarboxylic acid and maleic anhydride. The degradable polymer may be a general degradable polymer and may be reacted with a ligand, and it is more preferable that the degradable polymer is the above-listed degradable polymer.

The ligand contains carbon-carbon double bonds (=), the carbon-carbon double bonds can provide lone pair electrons required by radical reaction, and the carbon-carbon double bonds can generate radical reaction with the degradable polymer to obtain the ligand-degradable polymer under the action of illumination, radiation, peroxide and the like, and the specific reaction is shown as the reaction formulas (1) and (2).

Wherein the wavy line represents a degradable polymer and R represents H or a hydrocarbon group.

In some embodiments, the ligand does not contain a carbon-carbon double bond (=), and the ligand is combined with a compound containing a carbon-carbon double bond and then reacted with a degradable polymer to obtain the ligand-degradable polymer. Specifically, the ligand is at least one selected from the group consisting of acids, esters, amides, amines, amino acids, peptides, and proteins. The compound containing a carbon-carbon double bond is at least one selected from the group consisting of vinyl isocyanate, ethylene acetic acid, vinyl acetate, vinyl sulfonic acid, vinyl versatate, ethylene sorbate, acrylic acid, methyl acrylate, and acrylamide.

Of course, in some embodiments, the first reactive group grafted degradable polymer can also be used as a degradable polymer intermediate to react with a ligand containing a second reactive group to obtain a ligand-degradable polymer. The first reactive group can react with the second reactive group. At least one of the first reactive group and the second reactive group is capable of releasing a coordinating group. Furthermore, one of the first reactive group and the second reactive group is selected from at least one of an isocyanate group, a carboxyl group, an acid chloride group and an epoxy group, and the other is selected from at least one of an amino group, a hydroxyl group, a mercapto group and a carboxyl group. Of course, the first reactive group and the second reactive group are not limited to the above-mentioned groups, and may be those which react with each other to modify the ligand-degradable polymer and release a coordinating group which reacts with a metal ion or a solid corrosion product in a physiological environment to form a water-soluble coordination compound.

Specifically, one of the first reactive group and the second reactive group is an amino group, and the other one is at least one of an isocyanate group, a carboxyl group, an acyl chloride group and an epoxy group; one of the first reaction group and the second reaction group is a hydroxyl group, and the other one is at least one of an isocyanate group, a carboxyl group, an acyl chloride group and an epoxy group; one of the first reaction group and the second reaction group is a mercapto group, and the other one is at least one of an isocyanate group, a carboxyl group, an acyl chloride group and an epoxy group; one of the first reaction group and the second reaction group is a carboxyl group, and the other one is at least one of an isocyanate group, a carboxyl group, an acyl chloride group and an epoxy group; one of the first reactive group and the second reactive group is an isocyanate group, and the other one is at least one of an amino group, a hydroxyl group, a mercapto group and a carboxyl group; one of the first reactive group and the second reactive group is a carboxyl group, and the other one is at least one of an amino group, a hydroxyl group, a sulfhydryl group and a carboxyl group; one of the first reactive group and the second reactive group is an acyl chloride group, and the other is at least one of an amino group, a hydroxyl group, a sulfhydryl group and a carboxyl group; one of the first reactive group and the second reactive group is an epoxy group, and the other is at least one of an amino group, a hydroxyl group, a mercapto group and a carboxyl group. The reaction formula of the reaction between at least one of an amino group, a hydroxyl group, a mercapto group, and a carboxyl group and at least one of an isocyanate group, a carboxyl group, an acid chloride group, and an epoxy group is represented by the following expressions (3) to (11).

In the expressions (3) to (11), R, R' each independently represents H or a hydrocarbon group.

In some embodiments, the ligand contains at least one of amino, hydroxyl, thiol, and carboxyl groups, and the ligand-degradable polymer is obtained by reacting the ligand with a degradable polymer intermediate. The degradable polymer intermediate contains at least one of an isocyanate group, a carboxyl group, an acid chloride group and an epoxy group. Further, in the above-mentioned case, the ligand is selected from ethylenediamine, butanediamine, spermidine, spermine, triethylenetetramine, ethylenediaminetetraacetic acid, tetrasodium ethylenediaminetetraacetate, N ' - [5- [ [4- [ [5- (acetylhydroxyamino) pentyl ] ammonia ] -1, 4-dioxobutyl ] hydroxylamine ] pentyl ] -N- (5-aminopentyl) -N-hydroxysuccinamide (deferoxamine), 8-hydroxyquinoline, 8-hydroxyquinaldine, 4, 5-dihydroxybenzene-1, 3-disulfonic acid sodium salt, 4- [3, 5-dihydroxyphenyl-1H-1, 2, 4-triazole ] -benzoic acid (deferoxamine), 8-mercaptoquinoline, mercaptoacetic acid, methyl 5-methyl-2-mercaptobenzoate, oxalic acid, salts of N, N ' -bis- (5-hydroxyquinoline, N ' -bis- (5-hydroxyquinaldine), 4, 5-dihydroxybenzene-1, 3-disulfonic acid, and mixtures thereof tartaric acid, malic acid, succinic acid, oxaloacetic acid, fumaric acid, maleic acid, citric acid, nitrilotriacetic acid, diethylenetriamine pentacarboxylic acid, alginic acid, glutamic acid, aspartic acid, ornithine, lysine, maleic anhydride, acetic anhydride, maleic anhydride, succinic anhydride, maleic anhydride, phthalic anhydride, potassium citrate, calcium citrate, citric acid glyceride, acetylsalicylic acid, sulfosalicylamide, polyaspartic acid, polyglutamic acid, polyornithine, polylysine, and polymaleic anhydride.

The degradable polymer is grafted with at least one grafting compound containing isocyanate group, carboxyl group, acyl chloride group and epoxy group to obtain the degradable polymer intermediate. The graft compound is at least one selected from vinyl isocyanate, 3-isocyanic acid propylene, maleic anhydride, acrylic acid, methacrylic acid, decenoic acid, 9-decenoic acid undecylenic acid, acryloyl chloride, methacryloyl chloride, butenoyl chloride, fumaric chloride, undecylenic chloride, ethylene oxide, butylene oxide, and squalene oxide.

Of course, in some embodiments, the ligand contains at least one of an isocyanate group, a carboxyl group, an acid chloride group, and an epoxy group, and the ligand reacts with the degradable polymer intermediate to obtain the ligand-degradable polymer. The degradable polymer intermediate contains at least one of amino, hydroxyl, mercapto and carboxyl. Further, the ligand is selected from at least one of isocyanate, oxalic acid, tartaric acid, malic acid, succinic acid, oxaloacetic acid, fumaric acid, maleic acid, citric acid, nitrilotriacetic acid, diethylenetriamine pentacarboxylic acid, alginic acid, glutamic acid, aspartic acid, ornithine, lysine, maleic anhydride, acetic anhydride, maleic anhydride, succinic anhydride, maleic anhydride, phthalic anhydride, potassium citrate, calcium citrate, citric acid glyceride, acetylsalicylic acid, sulfosalicylamide, polyaspartic acid, polyglutamic acid, polyornithine, polylysine, polymaleic anhydride, acetyl chloride, oxalyl chloride, acetylsalicylic acid chloride, succinic acid monomethyl chloride, succinic acid monoethyl chloride, epoxy acetic acid, epoxy propionic acid and epoxy succinic acid.

The degradable polymer is grafted with at least one grafting compound containing amino, hydroxyl, sulfydryl and carboxyl to obtain a degradable polymer intermediate. The graft compound is at least one selected from the group consisting of aminoethylene, aminopropene, tetrakis (dimethylamino) ethylene, 2-amino-4-pentenoic acid, 10-hydroxy-2-decenoic acid, p-hydroxystyrene, 1, 4-dihydroxy-2-butene, 3-buten-1-ol, mercaptopropionic acid, mercaptoacrylic acid, 3-ene carboxylic acid, cyclohexene carboxylic acid, stilbene dicarboxylic acid, and pyrrolidone ene carboxylic acid.

In the medical device, the chemically modified ligand-degradable polymer is obtained by connecting the ligand to the chain segment of the degradable polymer, and then the modified degradable polymer is carried on the surface of the absorbable corrodible metal matrix. After the medical appliance is implanted into a body, the modified degradable polymer is gradually degraded and releases a coordination group, the coordination group and a corrosion product corroded by a corrodible metal matrix generate a coordination reaction in a physiological environment to generate a water-soluble coordination compound, so that the concentration of free metal ions and an insoluble solid corrosion product generated by corrosion of the corrodible metal matrix are reduced, the cytotoxicity risk of the metal ions is reduced, the corrosion of the metal is accelerated, the corrosion product can be quickly absorbed and metabolized by tissues, the recovery of a diseased part is facilitated, and the possibility of adverse reaction caused by the fact that the corrosion product stays in a human body for a long time is reduced.

In the following examples, the weight average molecular weight of the ligand-degradable polymer was measured by: the weight average molecular weight of the ligand-degradable polymer was measured using a GPC-multiangle laser light scattering apparatus of Wyatt, USA, in combination with a molecular weight measuring system. The test system included a liquid phase pump and injector from Agilent, inc. USA, an Agilent PL MIXED-C GPC column (size: 7.5X 300mm,5 microns), a multi-angle laser light scattering apparatus from Wyatt, USA, and a differential detector. The detection conditions are as follows: mobile phase: tetrahydrofuran; the pump flow rate: 1mL/min; sample introduction amount: 100 mu L of the solution; laser wavelength: 663.9nm; and (3) testing temperature: 35 ℃ is carried out.

In the following examples, the mass fraction of the ligand in the ligand-degradable polymer is defined as the ratio between the molecular mass of the ligand and the total molecular mass of the ligand-degradable polymer.

The method for detecting the mass fraction of the ligand comprises the following steps: and respectively detecting the molar ratio of the key groups in the ligand to the key groups of the degradable polymer molecules by a Magnetic Resonance Imaging (MRI), and calculating according to the ratio to obtain the mass fraction of the ligand.

The concentrations of the water-soluble complex compounds at the different stages were measured by the following methods: soaking the medical instruments in phosphate buffer solution (PBS for short) with the pH value range of 7.4 +/-0.05, and enabling the ratio of the volume of the PBS to the enclosed volume of the medical instruments to be 5-10, wherein the medical instruments need to be completely soaked in the PBS, and if the soaking containers of the medical instruments are small and large, the number of the medical instruments can be increased. The physiological solution soaked with the medical appliance is placed in a thermostatic water bath environment at 37 +/-1 ℃ and is oscillated at the speed of 40 revolutions per minute to 80 revolutions per minute. At a predetermined observation time point, such as 7 days, 1 month, 3 months, \8230;, filtration with an aqueous membrane having a pore size of 0.22 μm was performed to remove poorly soluble substances in PBS, and then the mass concentration of metal elements in the filtrate after filtration was measured by atomic absorption spectroscopy (AAS for short), and the mass concentration of PBS of the water-soluble complex compound at 37. + -. 1 ℃ was further obtained by conversion. At the same time, the corroded medical instrument is placed in the PBS solution with the same volume for further corrosion until the next observation time point, and the experimental process is as described above. If the metal element is detected in the solution after the solution is changed for a period of time, the coordination group is gradually released along with the degradation of the degradable polymer.

In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention are described in further detail below with reference to specific examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

The present invention will be described in further detail with reference to the following specific examples, which are not intended to limit the scope of the present invention.

It is to be noted that, in the following examples, the concentration of the iron complex detected in actual tests fluctuates within a certain range due to normal fluctuations in the performance of the product itself within the design-permitted range, differences in the corrosion rates of individual instruments, and systematic errors inevitably introduced by the test methods.

Example 1

The medical device provided by the embodiment 1 is an absorbable nitriding iron-based stent, which comprises a stent substrate made of nitriding iron material and a (2-amino-4-pentenoic acid) -poly-racemic lactic acid (mPDLLA for short) coating covering the surface of the stent substrate, wherein the wall thickness of the stent substrate is 50 microns, and the thickness of the coating is 60 microns. The volume ratio of the coating to the stent matrix is 10.56:1. the coating covers 100% of the surface of the stent matrix.

The manufacturing process of the absorbable nitriding iron-based bracket provided by the embodiment 1 is as follows: mPDLLA is dissolved in ethyl acetate, and the solution is sprayed on the surface of the nitriding iron-based bracket and dried to obtain the nitriding iron-based bracket of the example 1.

The preparation method of mPDLA comprises the following steps: mixing the components in a mass ratio of 50:50: dissolving 5 poly-racemic lactic acid (PDLLA), 2-amino-4-pentenoic acid and DCP in tetrahydrofuran, stirring at 60 deg.C under anhydrous and oxygen-free environment for 15 hr to obtain mPDLLA, purifying with methanol-chloroform system, and drying. The mPDLA used in example 1 was obtained. The molecular structural formula of mPDLA is shown as follows.

In the preparation process, the ligand 2-amino-4-pentenoic acid contains carbon double bonds, and the 2-amino-4-pentenoic acid is covalently grafted on the PDLLA chain segment through double bond free radical reaction to form the modified PDLLA.

The weight average molecular weight of mPDLLA used in example 1 was measured to be 20 ten thousand Da. The mass fraction of the ligand in mPDLA is 46%.

Using the same raw materials and methods, 5 identical absorbable iron-based scaffolds were made and 5 scaffolds were soaked together in PBS at 5 scaffold volumes. The PBS soaked with the scaffold was then placed in a 37 ℃ thermostatic water bath environment and shaken at a rate of 80 rpm. The concentration of the iron complex in PBS was then detected by AAS at 7 days, 1 month, and 3 months of shaking, respectively. The detection results are as follows: after the medical device of example 1 was immersed in PBS at 37 ℃ for 7 days, the concentration of the iron complex in PBS was 146mg/L. After 1 month of immersion, the concentration of the iron complex in PBS was 650mg/L. After 3 months of immersion, the concentration of the iron complex in PBS was 1500mg/L.

Example 2

Example 2 provides an absorbable iron-based stent, including a stent substrate made of pure iron material, and a salicylic acid-vinyl isocyanate-polylactic acid-glycolic acid copolymer (abbreviated as mPLGA) coating covering the surface of the stent substrate. The wall thickness of the stent substrate was 70 μm and the thickness of the mPLGA coating was 4 μm. The volume ratio of the coating to the stent matrix is 0.17. The coating covers 70% of the surface of the stent matrix.

Example 2 provides an absorbable iron-based stent prepared by the following steps: the mPLGA was uniformly applied to the surface of the pure iron stent by spraying, and the absorbable iron-based stent of example 2 was obtained.

The preparation method of mPLGA comprises the following steps: mixing a mixture of 1:1, dissolving salicylic acid and vinyl isocyanate in chloroform, uniformly mixing, keeping room temperature, stirring and reacting for 12 hours, and drying the obtained product, namely the vinyl isocyanate-salicylic acid in vacuum for later use; polylactic acid-glycolic acid copolymer (PLGA for short), vinyl isocyanate-acetylsalicylic acid and BPO in a mass ratio of 70:30:2 in toluene, and the mixture is stirred and reacted for 6 hours at 110 ℃ in an anhydrous and oxygen-free environment, and the obtained product is mPLGA, and the mPLGA used in the example 1 is obtained after purification and drying by a methanol-chloroform system. The molecular structural formula of mPLGA is shown below.

In the preparation process, firstly, vinyl isocyanate containing double bonds is grafted on ligand salicylic acid, and the vinyl isocyanate is participated in free radical reaction through the double bonds and is grafted on PLGA chain segments.

The weight average molecular weight of mPLGA used in example 2 was determined to be 15 ten thousand Da, with a mass fraction of ligand of 30%.

Using the same raw materials and methods, 5 identical absorbable iron-based scaffolds were made and 5 scaffolds were soaked together in PBS at 5 scaffold volumes. The PBS soaked with the scaffold was then placed in a 37 ℃ thermostatic water bath environment and shaken at a rate of 60 rpm. The concentration of the iron complex in PBS was then determined by AAS at 7 days, 1 month and 3 months of shaking, respectively. The detection results are as follows: after the medical device of example 2 was soaked in PBS at 37 ℃ for 7 days, the concentration of the iron complex in PBS was 50mg/L. After 1 month of immersion, the concentration of the iron complex in PBS was 300mg/L. After 3 months of immersion, the concentration of the iron complex in PBS was 1000mg/L. The results show that by grafting salicylic acid onto polylactic acid, the ligand can exist for a long time and be gradually released, and the ligand is chelated with iron ions to generate chelated iron, so that solid corrosion products are reduced.

Example 3

Example 3 provides an absorbable iron-based stent, comprising a stent substrate made of pure iron material, and a glycine-maleic anhydride-polycaprolactone (mPCL) coating covering the surface of the stent substrate. The wall thickness of the stent base was 50 μm and the thickness of the mPCL coating was 6 μm. The volume ratio of the coating to the stent matrix is 0.54. The coating covers 100% of the surface of the stent matrix.

The absorbable iron-based stent provided in example 3 was fabricated as follows: the mPCL was uniformly applied to the surface of the pure iron stent by spraying, resulting in the absorbable iron-based stent of example 3.

The preparation method of mPCL comprises the following steps: and (3) mixing the components in a mass ratio of 90:10:0.5 of Polycaprolactone (PCL), maleic Anhydride (MAH) and Benzoyl Peroxide (BPO) are dissolved in chloroform and mixed uniformly to obtain a mixture. Drying the mixture, reacting for 10 hours at 100 ℃ under the protection of nitrogen, purifying the obtained product by a methanol-chloroform system, and then drying in vacuum to obtain a modified polycaprolactone intermediate (maleic anhydride-polycaprolactone). The obtained maleic anhydride-polycaprolactone was dissolved in tetrahydrofuran, and then dropwise added to a tetrahydrofuran solution of glycine (glycine) to obtain a crude product of mPCL, which was purified with a methanol-chloroform system and dried to obtain mPCL used in example 3. The molecular structural formula of mPCL is shown as follows.

In the preparation process, maleic anhydride containing carbon double bond is grafted on polycaprolactone through free radical reaction to obtain modified polycaprolactone intermediate, which contains carboxyl, and the carboxyl reacts with amino in ligand amino acid to obtain glycine-maleic anhydride-polycaprolactone.

The weight average molecular weight of the mPCL used in example 3 was determined to be 10 ten thousand Da, and the mass fraction of the ligand was 20%.

Using the same raw materials and methods, 5 identical absorbable iron-based scaffolds were made and 5 scaffolds were soaked together in PBS at 5 scaffold volumes. The PBS soaked with the scaffold was then placed in a 37 ℃ thermostatic water bath environment and shaken at a rate of 60 rpm. The solubility of the iron complex in PBS was then examined by AAS at 7 days, 1 month and 3 months of shaking, respectively. The detection results are as follows: after the medical device of example 3 was immersed in PBS at 37 ℃ for 7 days, the concentration of the iron complex compound in PBS was 20mg/L. After 1 month of immersion, the concentration of the iron complex in PBS was 100mg/L. After 3 months of immersion, the concentration of the iron complex in PBS was 500mg/L. The results show that by grafting glycine onto polycaprolactone, glycine can be present for a long period and gradually released and chelate with iron ions to form iron chelates, reducing solid corrosion products.

Example 4

The medical device provided in embodiment 4 is an absorbable iron-based stent, which includes a stent substrate made of nitrided iron material, and a rapamycin- (8-hydroxyquinoline-2-carboxylic acid) -acryloyl chloride-polyglycolic acid (mPGA for short) coating covering the surface of the stent substrate, wherein the wall thickness of the stent substrate is 60 μm, and the thickness of the coating is 20 μm. The volume ratio of the coating to the stent matrix is 1. The coating covers 50% of the surface of the stent matrix.

Example 4 provides an absorbable iron-based stent prepared by the following steps: and (2) mixing the components in a mass ratio of 5: 1. the mPGA and the rapamycin are mixed and dissolved in ethyl acetate, and the solution is sprayed on the surface of the pure iron stent and dried to obtain the absorbable iron-based alloy stent of the embodiment 4.

The preparation method of mPGA comprises the following steps: mixing a mixture of 1: dissolving 8-hydroxyquinoline-2-carboxylic acid and acryloyl chloride of 1 in chloroform, uniformly mixing, keeping room temperature, stirring and reacting for 12 hours, and drying the obtained product 8-hydroxyquinoline-2-carboxylic acid-acryloyl chloride in vacuum for later use; polyglycolic acid (PGA), 8-hydroxyquinoline-2-carboxylic acid-acryloyl chloride and dicumyl peroxide (DCP) in a mass ratio of 60: 40:3 in toluene, and the mixture is stirred and reacted for 6 hours at 110 ℃ in an anhydrous and oxygen-free environment, and the obtained product is mPLA, and the mPGA used in the example 4 is obtained after purification and drying by a methanol-chloroform system. The molecular structural formula of mPGA is shown below.

In the modification process, acryloyl chloride containing double bonds is grafted on ligand 8-hydroxyquinoline-2 carboxylic acid, and the acryloyl chloride participates in free radical reaction through the double bonds and is grafted on the PGA chain segment. The (8-hydroxyquinoline-2-carboxylic acid) -acryloyl chloride-polyglycolic acid can be gradually degraded in vivo, and simultaneously the ligand 8-hydroxyquinoline-2-carboxylic acid is gradually released and chelated with iron ions to generate the 8-hydroxyquinoline-2-carboxylic acid iron.

The weight average molecular weight of the mPLA used in example 4 was measured to be 10 ten thousand Da, and the mass fraction of the ligand was 37%.

Using the same raw materials and methods, 5 identical resorbable iron-based scaffolds were made and 5 scaffolds were soaked together in PBS at 5 scaffold volumes. The PBS soaked with the scaffold was then placed in a 37 ℃ thermostatic water bath environment and shaken at a rate of 60 rpm. The solubility of the iron complex in PBS was then examined by AAS at 7 days, 1 month and 3 months of shaking, respectively. The detection results are as follows: after the medical device of example 4 was soaked in PBS at 37 ℃ for 7 days, the concentration of the iron complex in PBS was 100mg/L. After 1 month of immersion, the concentration of the iron complex in PBS was 400mg/L. After 3 months of immersion, the concentration of the iron complex in PBS was 1000mg/L. The results show that by grafting the ligand onto polyglycolic acid, the ligand can be present for a long period of time and gradually released and chelated with iron ions to form chelated iron, reducing solid corrosion products.

Example 5

The medical device provided by embodiment 5 is an iron-based absorbable nitriding stent, which comprises a stent substrate made of a nitriding iron material, a zinc layer covering the surface of the stent substrate, and an ethylene diamine tetraacetic acid-acryloyl chloride-polylactic acid (abbreviated as mPLA) coating covering the surface of the zinc layer, wherein the wall thickness of the stent substrate is 50 μm, the thickness of the zinc layer is 1.5 μm, and the thickness of the coating is 10 μm. The volume ratio of the coating to the zinc layer to the stent matrix is 1.13. The coating covers 100% of the surface of the stent matrix. The zinc layer covers 100% of the surface of the stent matrix.

The manufacturing process of the absorbable nitriding iron-based bracket provided by the embodiment 5 is as follows: covering a zinc layer on the surface of the nitrided iron-based bracket by an electroplating method; then mPLA is dissolved in ethyl acetate, and the solution is sprayed on the surface of the galvanized iron-based bracket and dried to obtain the absorbable nitriding iron-based bracket of example 5.

The preparation method of mPLA comprises the following steps: mixing the components in a molar ratio of 1: dissolving ethylenediaminetetraacetic acid (EDTA) and acryloyl chloride of 1 in chloroform, uniformly mixing, keeping room temperature, stirring and reacting for 12 hours, and carrying out vacuum drying on the obtained product, namely ethylenediaminetetraacetic acid-acryloyl chloride for later use; polylactic acid (PLA for short), ethylene diamine tetraacetic acid-acryloyl chloride and di-tert-butyl peroxide (DBP) in a mass ratio of 35:65: 6. dissolving in toluene, stirring and reacting at 120 ℃ under anhydrous and oxygen-free environment for 18 hours to obtain a product mPLA, purifying by a methanol-chloroform system, and drying to obtain mPLA used in example 5. The molecular structural formula of mPLA is shown as follows.

In the modification process, acryloyl chloride containing double bonds is grafted on a ligand ethylene diamine tetraacetic acid, and the acryloyl chloride participates in free radical reaction through the double bonds and is grafted on a PLA chain segment. The EDTA-acryloyl chloride-polylactic acid can be gradually degraded in vivo, and meanwhile, the ligand EDTA is gradually released and chelated with iron ions to generate EDTA iron.

The weight average molecular weight of the mPLA used in example 5 was measured to be 20 ten thousand Da, and the mass fraction of the ligand was 60%.

Using the same raw materials and methods, 5 identical absorbable iron-based scaffolds were made and 5 scaffolds were soaked together in PBS at 5 scaffold volumes. The PBS soaked with the scaffold was then placed in a 37 ℃ thermostatic water bath environment and shaken at a rate of 60 rpm. The solubility of the iron complex in PBS was then examined by AAS at 7 days, 1 month, and 3 months of shaking, respectively. The detection results are as follows: after the medical device of example 5 was immersed in PBS at 37 ℃ for 7 days, the concentrations of the zinc and iron complexes in PBS were 300mg/L and 0mg/L, respectively. After soaking for 1 month, the concentrations of the zinc and iron coordination compounds in PBS are respectively 200mg/L and 400mg/L. After 3 months of soaking, the concentrations of the zinc and iron coordination compounds in PBS are respectively 200mg/L and 1200mg/L. The results show that by grafting the ligand to the polyester, the ligand can be present for a long time and gradually released, the free zinc ion concentration is reduced by chelating with zinc ions in the early stage, and the iron solid corrosion products are reduced by chelating with iron ions in the middle and later stages.

Example 6

The medical device provided by the embodiment 6 is an absorbable nitriding iron-based stent, which comprises a stent substrate made of nitriding iron material and a glucan-poly (racemic lactic acid) (mPDLA for short) coating layer covering the surface of the stent substrate, wherein the wall thickness of the stent substrate is 50 μm, and the thickness of the coating layer is 20 μm. The volume ratio of the coating to the stent matrix is 2.24. The coating covers 100% of the surface of the stent matrix.

Example 6 provides a fabrication process of an iron-based absorbable nitrided stent, which comprises the following steps: covering a zinc layer on the surface of the nitrided iron-based bracket by an electroplating method; and then dissolving glucan-poly (racemic lactic acid) (mPDLLA for short) in ethyl acetate, spraying the solution on the surface of the galvanized iron-based stent, and drying to obtain the absorbable and nitrided iron-based stent of the example 6.

The preparation method of mPDLA comprises the following steps: mixing the components in a molar ratio of 1:1, dissolving dextran 5W and PDLLA in dimethyl sulfoxide, and carrying out copolymerization reaction under the activation of epichlorohydrin to obtain a product dextran-PDLLA, namely mPDLA, and purifying and drying the product dextran-PDLLA by acetone to obtain the mPDLA used in the example 6. The molecular structural formula of mPDLA is shown as follows.

In the modification process, the two structural units of glucan and poly-racemic lactic acid are randomly and alternately connected. The glucan-poly-dl-lactic acid is gradually degraded in vivo, and the glucan is gradually degraded and released to be chelated with iron corrosion products to form a glucan-iron complex.

The weight average molecular weight of the mPLA used in example 6 was measured to be 20 ten thousand Da, and the mass fraction of the ligand was 50%.

Using the same raw materials and methods, 5 identical absorbable iron-based scaffolds were made and 5 scaffolds were soaked together in PBS at 5 scaffold volumes. The PBS soaked with the scaffold was then placed in a 37 ℃ thermostatic water bath environment and shaken at a rate of 60 rpm. The solubility of the iron complex in PBS was then examined by AAS at 7 days, 1 month and 3 months of shaking, respectively. The detection results are as follows: after the medical device of example 5 was immersed in PBS at 37 ℃ for 7 days, the concentrations of the iron complex compounds in PBS were 500mg/L, respectively. After 1 month of immersion, the concentrations of the iron complexes in PBS were 1000mg/L, respectively. After 3 months of immersion, the concentrations of the iron complexes in PBS were 1800mg/L, respectively. The results show that by copolymerizing the ligand with the polyester, the ligand can be present for a long period of time and gradually released, chelating the iron ions to reduce iron solid corrosion products.

Comparative example 1

And spraying common PLA on the surface of the pure iron stent, and drying to obtain the absorbable iron-based stent of the comparative example 1. The wall thickness of the stent matrix was 50 μm and the thickness of the PDLLA coating was 5 μm. The mass ratio of the coating to the stent matrix is 0.44. The coating covers 100% of the surface of the stent matrix.

The weight average molecular weight of the PDLLA used in comparative example 1 was measured to be 20 ten thousand Da by the aforementioned detection method.

Using the same raw materials and methods, 5 identical resorbable iron-based scaffolds were made and 5 scaffolds were soaked together in PBS at 5 scaffold volumes. The PBS soaked with the scaffold was then placed in a 37 ℃ thermostatic water bath environment and shaken at a rate of 80 rpm. The solubility of the iron complex in PBS was then examined by AAS at 7 days, 1 month and 3 months of shaking, respectively. The detection results are as follows: the absorbable iron-based stent of comparative example 1 was immersed in a PBS solution at 37 ℃ for 7 days, and the concentration of the iron complex in PBS was 0mg/L. After 1 month of immersion, the concentration of the iron complex in PBS was 0mg/L. After 3 months of immersion, the concentration of the iron complex in PBS was 0mg/L.

The results show that compared with the medical device provided in example 1, the absorbable iron-based stent in comparative example 1 generates insoluble corrosion products in physiological environment because the common polylactic acid in comparative example 1 cannot perform coordination reaction with iron ions under physiological conditions. In the medical device provided in example 1, polylactic acid is chemically modified to form ligand-polylactic acid having a ligand group, and the ligand-polylactic acid is bound to iron ions in a physiological environment to form a water-soluble iron complex.

Comparative example 2

And spraying a common 2-amino-4-pentenoic acid coating on the surface of the pure iron stent, then spraying a PDLLA coating, and drying to obtain the absorbable iron-based stent of the comparative example 2. The wall thickness of the stent matrix was 50 μm, the thickness of the 2-amino-4-pentenoic acid coating was 5 μm, and the thickness of the PDLLA coating was 5 μm. The mass ratio of the coating to the stent matrix is 0.96. The coating covers 100% of the surface of the stent matrix.

By the foregoing examination method, the weight average molecular weight of PLA used in comparative example 2 was measured to be 20 ten thousand Da, and the mass fraction of 2-amino-4-pentenoic acid was 50%.

Using the same raw materials and methods, 5 identical absorbable iron-based scaffolds were made and 5 scaffolds were soaked together in PBS at 5 scaffold volumes. The PBS soaked with the scaffold was then placed in a 37 ℃ thermostatic water bath environment and shaken at a rate of 80 rpm. The solubility of the iron complex in PBS was then examined by AAS at 7 days, 1 month and 3 months of shaking, respectively. The detection results are as follows: the absorbable iron-based stent of comparative example 2 was immersed in a PBS solution at 37 ℃ for 7 days, and the concentration of the iron complex in PBS was 50mg/L. After 1 month of immersion, the concentration of the iron complex in PBS was 0mg/L. After 3 months of immersion, the concentration of the iron complex in PBS was 0mg/L.

The results show that compared with the medical device provided in example 1, the absorbable iron-based stent of comparative example 2 has the advantages that due to the mere physical blending between the polylactic acid and the ligand of comparative example 2, the ligand is rapidly diffused in the body fluid and cannot exist on the surface of the stent for a long time. Can chelate a small amount of iron ions in the early stage, has no ligand in the middle and later stages after liquid change, and generates no water-soluble chelated iron. And because the ligand has poor film forming property, a thicker film is difficult to form on the surface of the corrodible metal matrix, the coordination capacity is small, and only a small amount of iron can be chelated.

Compared with the method of only physically blending polylactic acid and the ligand in the comparative example 2, the chemical modification method in the example 1 can ensure that the ligand in the ligand-degradable polyester is distributed more uniformly, the binding force is stronger, the coordination capacity is large, the ligand is ensured to exist stably and play a role, and the loss of the ligand caused by body fluid soaking or scouring is avoided.

In summary, in the medical device of the present invention, a ligand is grafted on a segment of a degradable polymer through a covalent bond to obtain a chemically modified ligand-degradable polymer, and then the ligand-degradable polymer is carried on the surface of a corrodible metal matrix, and a water-soluble coordination compound is generated in a physiological environment by combining a coordination group in the ligand-degradable polyester with a corrosion product generated by corrosion of the corrodible metal matrix, so that an insoluble solid corrosion product generated by corrosion of the corrodible metal matrix is reduced, and the water-soluble corrosion product of the corrodible metal matrix can be rapidly absorbed by tissues and metabolized.

In addition, as the ligand is combined with the degradable polymer through covalent bonds, the combination mode between the ligand and the degradable polymer is firmer and more reliable, and the ligand can be more uniformly distributed in the ligand-degradable polymer, thereby avoiding the loss of the ligand caused by body fluid scouring or soaking.

Claims

1. A medical device comprising a corrodible metal substrate and a ligand-degradable polymer, the ligand-degradable polymer being obtainable by reacting a degradable polymer with a ligand, the ligand-degradable polymer being capable of degrading and releasing a coordinating group capable of coordinating with a corrosion product produced by the corrodible metal substrate in a physiological environment to form a water-soluble coordination compound.

2. The medical device of claim 1, wherein the corrodible metal matrix is at least one material selected from the group consisting of Fe, zn, mg, iron alloys, zinc alloys, and magnesium alloys.

3. The medical device of claim 2, wherein the ferrous alloy is at least one of an iron-carbon alloy and a nitrided iron alloy.

4. The medical device of claim 1, wherein said degradable polymer is selected from degradable polyesters.

5. The medical device of claim 4, wherein the degradable polyester is selected from at least one of polylactic acid, polyglycolic acid, polycaprolactone, polyhydroxyalkanoate, polyacrylate, polybutylene succinate, poly (beta-hydroxybutyrate), polydioxanone, and polytrimethylene carbonate.

6. The medical device of claim 4, wherein the degradable polyester is selected from degradable copolymers, wherein the degradable copolymers are selected from copolymers formed by copolymerization of at least two of monomers forming polylactic acid, polyglycolic acid, polylactic glycolic acid, polycaprolactone, polyhydroxyalkanoate, polyacrylate, polysuccinate, poly (beta-hydroxybutyrate), polydioxanone, and polytrimethylene carbonate.

7. The medical device of claim 1, wherein the solubility of the water-soluble coordination compound in phosphate buffered saline at 36 ℃ to 38 ℃ is greater than or equal to 10mg/L.

8. The medical device according to claim 1, wherein the volume ratio of the ligand-degradable polymer to the corrodible metal matrix is 0.1.

9. The medical device of claim 1, wherein the corrodible metal matrix comprises 50-90% by weight of the medical device.

10. The medical device according to claim 1, wherein the ligand-degradable polymer comprises 5 to 80% by mass of the ligand.

11. The medical device of claim 1, wherein the coordinating group comprises at least one of an amino group, a carboxyl group, a cyanide group, a thiocyanate group, an isothiocyanide group, a nitro group, a hydroxyl group, a mercapto group, an aromatic heterocyclic group, a nitroso group, a sulfo group, a phosphate group, and an organophosphine group.

12. The medical device of claim 1, wherein the ligand is a polysaccharide.

13. The medical device of claim 1, wherein said ligand is a multidentate ligand having at least two coordinating groups.

14. The medical device of claim 13, wherein said multidentate ligand is selected from at least one of amino or carboxyl-containing amino acids, oligopeptides, polypeptides, proteins, polyamines, anhydrides and polyanhydrides.

15. The medical device according to claim 1, wherein said ligand contains a carbon-carbon double bond, and said ligand-degradable polymer is generated by radical reaction of said carbon-carbon double bond with said degradable polymer, and said carbon-carbon double bond provides a lone electron pair required for radical reaction.

16. The medical device of claim 15, wherein the carbon-carbon double bond-containing ligand is selected from at least one of 2-amino-4-pentenoic acid, 2-acetamidoacrylic acid, maleic acid, fluoroelenic acid, allyl oxalate, octenylsuccinic acid, diethylenetriaminepentacarboxylic acid, and maleic anhydride.

17. The medical device of claim 1, wherein the ligand is bound to a compound having a carbon-carbon double bond and then reacted with the degradable polymer to form the ligand-degradable polymer.

18. The medical device of claim 17, wherein the ligand is selected from at least one of an acid, an ester, an amide, an amine, an amino acid, a peptide, a protein, an anhydride, and a polyanhydride, and the compound having a carbon-carbon double bond is selected from at least one of vinyl isocyanate, ethylene acetic acid, vinyl acetate, vinyl sulfonic acid, vinyl versatate, ethylene sorbate, acrylic acid, methyl acrylate, and acrylamide.

19. The medical device according to claim 1, wherein the ligand-degradable polymer is obtained by grafting a first reactive group to a degradable polymer as a degradable polymer intermediate, the degradable polymer intermediate being reacted with a ligand having a second reactive group, the first reactive group being capable of reacting with the second reactive group, at least one of the first reactive group and the second reactive group being capable of releasing a coordinating group.

20. The medical device of claim 19, wherein one of the first reactive group and the second reactive group is selected from at least one of an isocyanate group, a carboxyl group, an acid chloride group, and an epoxy group, and the other is selected from at least one of an amino group, a hydroxyl group, a thiol group, and a carboxyl group.

21. The medical device of claim 20, wherein the ligand comprises at least one of an amino group, a hydroxyl group, a thiol group, and a carboxyl group, and the degradable polymer is combined with a compound having a carbon-carbon double bond to form a degradable polymer intermediate, wherein the degradable polymer intermediate comprises at least one of an isocyanate group, a carboxyl group, an acid chloride group, and an epoxy group, and wherein the ligand-degradable polymer is obtained by reacting the ligand with the degradable polymer intermediate.

22. The medical device of claim 20, wherein the ligand comprises at least one of an isocyanate group, a carboxyl group, an acid chloride group, and an epoxy group, and the degradable polymer is combined with a compound having a carbon-carbon double bond to form a degradable polymer intermediate, wherein the degradable polymer intermediate comprises at least one of an amino group, a hydroxyl group, a thiol group, and a carboxyl group, and wherein the ligand-degradable polymer is obtained by reacting the ligand with the degradable polymer intermediate.

23. The medical device of claim 1, wherein the ligand-degradable polymer is at least partially in contact with the corrodible metal matrix, and wherein the ligand-degradable polymer forms a coating on the surface of the corrodible metal matrix or is contained in a pocket formed by the corrodible metal matrix.

24. The medical device of claim 1, wherein the medical device is loaded with an active drug.

25. The medical device of claim 1, wherein the medical device is a vascular stent, a non-vascular endoluminal stent, an occluder, an orthopedic implant, a dental implant, a respiratory implant, a gynecological implant, a male implant, a suture, or a bolt.